Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido{1,2-a}pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo{1,2-a}pyrimidin-5(1h)one derivatives

ABSTRACT

The invention relates to a pyrimidone derivative represented by formula (I) or a salt thereof wherein X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2  alkyl group and a hydrogen atom; Y represents a bond, an ethenylene group, an ethynylene group an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group, a carbonyl group, a hydroxyiminomethylene group, a dioxolan group, a nitrogen atom being optionally substituted; or a methylene group optionally substituted; or a methylene group optionally substituted; R1 represents a 2, 3 or 4-pyridine ring optionally substituted; R2 may represent a C 1-6  alkyl group optionally; a C 3-6  cycloalkyl group, a C 1-4  alkythio group, a C 1-4  alkoxy group, a C 1-2  perhalogenated alkyl group, a C 1-3  halogenated alkyl group, a phenylthio group, a benzyl group, a benzene ring, an indan ring, a 5,6,7,8-tetrahydronaphthalene ring, a naphthalene ring, a pyridine ring, a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring; R3 and R4 represent, each independently, a hydrogen atom, a C 1-6  alkyl group, a hydroxy group, a C 1-4  alkoxy group or a halogen atom; R5 represents a hydrogen atom, a C 1-6  alkyl group or a halogen atom; with the proviso that when R3 and R4 represent each a hydrogen atom then R5 is not a hydrogen atom. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β or GSK3β, and cdk5/p25, such as Alzheimer disease

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activities of GSK3βalone or by the combined effects of GSK3β and cdk5/p25.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral tauopathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β, ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway. Thus,it appears that inhibition of GSK3β activity may result in neurotrophicactivity. Indeed there is evidence that lithium, an non-competitiveinhibitor of GSK3β, enhances neuritogenesis in some models and alsoincreases neuronal survival, through the induction of survival factorssuch as Bcl-2 and the inhibition of the expression of proapoptoticfactors such as P53 and Bax. Recent studies have demonstrated thatβ-amyloid increases the GSK3β activity and tau protein phosphorylation.Moreover, this hyperphosphorylation as well as the neurotoxic effects ofβ-amyloid are blocked by lithium chloride and by a GSK3β antisense mRNA.These observations strongly suggest that GSK3β may be the link betweenthe two major pathological processes in Alzheimer's disease: abnormalAPP (Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Cdk5/p25, also known as tau protein kinase 2 (TPK2), is a prolinedirected Ser/Thr kinase essential for central nervous system developmentand in particular for neuronal migration and neurite outgrowth. Cdk5 isa homologue of cyclin-dependent kinases and rather ubiquitouslyexpressed. Its activator p35 (a 305 aa protein) or a truncated form p25(208 aa, missing an N-terminal proline-rich domain not required foractivity) are selectively expressed in neurons, limiting cdk5 kinaseactivity essentially to the CNS. Cdk5 is completely inactive in theabsence of p35 or p25. The term cdk5/p25 will be used here for theactive enzyme since evidence exists suggesting that p25 and less so p35may be involved in pathological processes.

Physiological substrates of cdk5/p25 include DARPP-32, Munc-18, PAK1,synapsin 1 and perhaps some others. In addition, it is now wellestablished that cdk5/p25 phosphorylates tau protein epitopes which arehyperphosphorylated in Alzheimer's disease. More recently, elevatedcdk5/p25 activity, mislocalization of cdk5 and an increase in p25activator has been found in the brain of Alzheimer patients.Interestingly, prephosphorylation of tau protein by cdk5/p25considerably enhances phosphorylation of tau by GSK3β on other epitopes,also found hyperphosphorylated in Alzheimer's disease. Moreover,neurofibrillary tangles, the hallmark of Alzheimer's disease, arelabeled with antisera for GSK3β and cdk5, but not GSK3α and MAP kinase,also, GSK3β and cdk5 are associated with microtubules and both, morethan PKA and CK, contribute to the AD-like phosphorylation of tauprotein. These results taken together suggest that mixed inhibitors ofGSK3β and cdk5/p25 should efficient in protecting tau protein fromhyperphosphorylation. Therefore, they would be useful in the treatmentof any pathological disorder associated with the abnormalphosphorylation of tau protein, in particular Alzheimer's disease, butalso other tauopathies (e.g. frontotemporoparietal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy).

Cdk5/p25 has been linked to apoptosis and neurodegeneration in moregeneral terms. Its overexpression induces apoptosis in cultured neurons,in brain tissue apoptotic cells show strong immunoreactivity for cdk5.Neurotoxic agents, incl. Aβ(1–42), neuronal injury, ischemia or growthfactor withdrawal lead to activation and mislocalization of cdk5/p25,abnormal phosphorylation of cdk5 substrates, cytoskeletal disruption andcell death. Moreover, phosphorylation by cdk5/p25 transforms DARPP-32into an inhibitor of protein kinase A, reducing signal transduction inthe striatum with obvious implications for Parkinson's disease. A rolefor cdk5 in ALS has also been proposed based on its ability tophosphorylate neurofilaments. More recently, deregulation of cdk5 wasdetected in a mouse model of amyotrophic lateral sclerosis.

Altogether, these experimental observations indicate that GSK3βinhibitors may find application in the treatment of theneuropathological consequences and the cognitive and attention deficitsassociated with Alzheimer's disease, as well as other acute and chronicneurodegenerative diseases. These include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy) and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; peripheralneuropathies; retinopathies and glaucoma.

In addition GSK3β inhibition may find application in the treatment ofother diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; cancers such asbreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors.

Since it appears that both, GSK3β and cdk5/p25 play a major role in theinduction of apoptosis in neuronal cells, combined inhibition of thesetwo enzymes may find application in the treatment of not onlyAlzheimer's disease and the other above-mentioned tauopathies, but alsoin a number of other neurodegenerative disorders, in particularParkinson's disease and amyotrophic lateral sclerosis; other dementiasincluding vascular dementia; acute stroke and other traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma.

In addition mixed TPK1/TPK2 inhibitors may find their applications inthe treatment of other diseases such as: smoking cessation and otherwithdrawal syndromes, epilepsy.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β or GSK3β and cdk5/p25activity, more particularly of neurodegenerative diseases. Morespecifically, the object is to provide novel compounds useful as anactive ingredient of a medicament that enables prevention and/ortreatment of neurodegenerative diseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides pyrimidone derivatives representedby formula (I) or salts thereof, solvates thereof or hydrates thereof:

wherein:

-   X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a    C₁₋₂ alkyl group and a hydrogen atom;-   Y represents a bond, an ethenylene group, an ethynylene group, an    oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group, a    carbonyl group, a hydroxyiminomethylene group, a dioxolan group, a    nitrogen atom being optionally substituted by a C₁₋₆ alkyl group, a    phenyl group or a benzyl group; or a methylene group optionally    substituted by one or two groups chosen from a C₁₋₆ alkyl group, a    benzyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂    perhalogenated alkyl group, an amino group, an acetylamino group or    a phenyl group;-   R1 represents a 2, 3 or 4-pyridine ring optionally substituted by a    C₃₋₆ cycloalkyl group, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a    benzyl group or a halogen atom;

when Y represents a bond, a methylene group optionally substituted, ahydroxyiminomethylene group, a dioxolan group or a carbonyl group thenR2 represents a C₁₋₆ alkyl group optionally substituted by a hydroxygroup, a C_(6,10) aryloxy or a C_(6,10) arylamino group; a C₃₋₆cycloalkyl group, a C₁₋₄ alkylthio group, a C₁₋₄alkoxy group, a C₁₋₂perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, a phenylthiogroup, a benzyl group, a benzene ring, an indan ring, a5,6,7,8-tetrahydronaphthalene ring, a naphthalene ring, a pyridine ring,a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring; thebenzyl group or the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylendioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, C₁₋₄ alkylsulfonyloxy group or a phenyl group;

when Y represents a ethenylene group, a ethynylene group, an oxygenatom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogenatom being optionally substituted then R2 represents a C₁₋₆ alkyl groupoptionally substituted by a hydroxy group, a C_(6,10) aryloxy or aC_(6,10) arylamino group; a C₃₋₆ cycloalkyl group, a C₁₋₂ perhalogenatedalkyl group, a C₁₋₃ halogenated alkyl group, a benzyl group, a benzenering, an indan ring, a 5,6,7,8-tetrahydronaphthalene ring, a naphthalenering, a C_(6,10) arylamino, a pyridine ring, a pyrrole ring, a thiophenering, a furan ring or an imidazole ring the benzyl group or the ringsbeing optionally substituted by 1 to 4 substituents selected from a C₁₋₆alkyl group, a methylendioxy group, a halogen atom, a C₁₋₂perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, a hydroxylgroup, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, a C₁₋₅monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C₆₋₁₀ arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, C₁₋₄ alkylsulfonyloxy group or a phenyl group;

-   R3 represents a hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group,    a C₁₋₄ alkoxy group or a halogen atom;-   R4 represents a hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group,    a C₁₋₄ alkoxy group or a halogen atom;-   R5 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;    with the proviso that when R3 and R4 represent each a hydrogen atom    then R5 is not a hydrogen atom;-   When m equals 0, p equals 1, 2 or 3,-   When m equals 1, p equals 0, 1 or 2,-   When m equals 2, p equals 0 or 1; and-   n represents 0 to 3.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β or GSK3β and cdk5/p25 activity, and the aforementionedmedicament which is used for preventive and/or therapeutic treatment ofneurodegenerative diseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; smoking cessation andother withdrawal syndromes, epilepsy; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,tauopathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma, and the aforementioned medicament in theform of pharmaceutical composition containing the above substance as anactive ingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β or GSK3βand cdk5/p25 activity comprising as an active ingredient a substanceselected from the group consisting of the pyrimidone derivatives offormula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β or GSK3β andcdk5/p25 activity, which comprises the step of administering to apatient a preventively and/or therapeutically effective amount of asubstance selected from the group consisting of the pyrimidonederivatives of formula (1) and the physiologically acceptable saltsthereof, and the solvates thereof and the hydrates thereof; and a use ofa substance selected from the group consisting of the pyrimidonederivatives of formula (I) and the physiologically acceptable saltsthereof, and the solvates thereof and the hydrates thereof for themanufacture of the aforementioned medicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen have been substituted by a halogeno, for example a CF₃or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by a halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₅ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

The C_(6,10) arylamino group represents an amino group substituted by aphenyl group or a naphthyl group;

The C_(6,10) aryloxy group represents a phenyloxy group and anaphthyloxy group.

The dioxolan group represents the following group:

The hydroxyiminomethylene group represents the following group:

The ethenylene group represents the divalent group of formula:

The ethynylene group represents the divalent group of formula:

The leaving group represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)-aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention. Thepyrimidone derivatives represented by the aforementioned formula (I) mayhave one or more asymmetric carbon atoms. As for the stereochemistry ofsuch asymmetric carbon atoms, they may independently be in either (R)and (S) configuration, and the pyrimidone derivative may exist asstereoisomers such as optical isomers, or diastereoisomers. Anystereoisomers in pure form, any mixtures of stereoisomers, racemates andthe like fall within the scope of the present invention.

Examples of preferred compounds of the present invention are shown intable 1 and table 2 hereinafter. However, the scope of the presentinvention is not limited by these compounds.

Preferred compounds of the present invention represented by formula (I)include also:

-   (1) Compounds wherein R1 represents a 3- or 4-pyridine ring and more    preferably 4-pyridine ring, which may be substituted by a C₁₋₂ alkyl    group, a C₁₋₂ alkoxy group or a halogen atom; and/or-   (2) X represents two hydrogen atoms, an oxygen atom or a C₁₋₂ alkyl    group and a hydrogen atom;-   (3) Y represents a bond, a carbonyl group, a hydroxyiminomethylene    group, a dioxolan group; or a methylene group optionally substituted    by one or two groups chosen from a C₁₋₆ alkyl group, a benzyl group,    a hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated alkyl    group, an amino group, an acetylamino group or a phenyl group.

More preferred compounds of the present invention represented by formula(I) include also:

-   (1) Compounds wherein R1 represents an unsubstituted 4-pyridine    ring;-   Particularly preferred compounds of the present invention    represented by formula (I) include compounds of table 1:-   1.    9-[3-(2-Fluorophenyl)-propyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   2.    9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   3.    9-(2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   4.    9-(2-Oxo-2-phenyl-ethyl)-7,7-difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   5.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-difluoro-2-(pyridin4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   6.    9-(2-Oxo-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   7.    9-[2-Oxo-2-(3-chlorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   8.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   9.    9-[2-Oxo-2-(3-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   10.    9-[2-Hydroxy-2-(3-chlorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   11.    9-[2-Hydroxy-2-(3-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-y)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   12.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   13.    9-[2-Oxo-2-(4-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   14.    9-[2-Oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   15.    9-[2-Oxo-2-(3-methoxyphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   16.    9-[2-Oxo-2-(4-phenylphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   17.    9-[2-(1-Methyl-2-oxo-2-(3,4-methylendioxy-5-methoxyphenyl)-ethyl)]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   18.    9-[2-Oxo-2-(4-chlorophenyl)ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   19.    9-[2-Oxo-2-(naphth-2-yl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   20.    9-[2-Oxo-2-(4-methylphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   21.    9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   22.    9-(2(S)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   23.    9-(3-Phenyl-propanoyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   24.    9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   25.    9-(2-Methoxy-2-phenyl-2-trifluoromethyl-ethanoyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   26.    9-(2-Hydroxy-2,2-diphenylethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   27.    9-(2-Hydroxyimino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   28.    9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   29.    7,7-Dimethyl-9-(2-phenyl-[1,3]dioxolan-2-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   30.    9-(2,3-Dihydroxypropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   31.    (2(R)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   32.    9-(2-Hydroxy-3-phenylaminopropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   33.    9-(2-Acetylamino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   34.    9-(2-Amino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   35.    9-(2-Hydroxy-3-phenoxypropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   36.    9-(2-Oxo-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   37.    9-[2-Oxo-2-(3-fluorophenyl)-ethyl]-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   38.    9-(2-Oxo-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   39.    9-(2-Oxo-2-phenyl-ethyl)-3-chloro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   40.    9-(2-Oxo-2-phenyl-ethyl)-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   41. 2-(7-Methyl-6-oxo-8-pyridinyl-3,4-dihydro-2H,6H    pyrimido[1,2-a]pyrimidin-1-yl)-N-phenyl-acetamide-   42.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-chloro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   43.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   44.    9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   45.    9-(2(S)-Methoxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   46.    9-(2(R)-Methoxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   47.    9-[3-(2-Fluorophenyl)propyl]-7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   48.    9-[3-(2-Fluorophenyl)propyl]-7-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   49.    9-(2-Oxo-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   50.    9-(2-Hydroxy-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   51.    9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   52.    9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   53.    9-(2(R)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8.9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   54.    3-Fluoro-9-[2-(4-fluoro-2-methoxy-phenyl)-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   55.    9-Indan-2-ylmethyl-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   56.    3-Fluoro-9-[2-(4-fluoro-2-methoxy-phenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   57.    9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;    and compounds of table 2:-   1.    [3-(2-Fluoro-phenyl)-propyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   2.    [2-Oxo-2-phenylethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   3.    [2-Hydroxy-2-phenylethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   4.    [2-Oxo-2-(4-chlorophenyl)ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   5.    [2-Oxo-2-(4-methylphenyl)ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   6.    [2-Oxo-4-phenylphenyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   7.    [1-Methyl-2-oxo-2-(3,4-methylendioxy-5-methoxyphenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   8.    [2-Oxo-2-(naphth-2-yl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   9.    [2-Oxo-2-(4-fluorophenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   10.    [2-Oxo-2-(3-methoxyphenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one-   11.    [2-Oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;    and compounds of table 3:-   1.    9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   2.    9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin8-4-y)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   3.    9-[2-(4-Fluoro-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   4.    8-Methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   5.    9-[2-(2,5-Dimethoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   6.    9-[2-(2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.-   7.    9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   8.    9-[2(S)-Hydroxy-2-phenyl-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   9.    8-Methyl-9-[naphthalen-1-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   10.    8,8-Dimethyl-9-[2-oxo-2-phenyl-ethyl]-2(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   11.    8-Methyl-9-[naphthalen-2-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   12.    9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   13.    9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   14.    8,8-Dimethyl-9-[2(S)-phenyl-propyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   15.    8,8-Dimethyl-9-[2(R)-phenyl-propyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   16.    8-Ethyl-9-[2-oxo-2-phenyl-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   17.    8-Ethyl-9-[2(S)-hydroxy-2-phenyl-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   18.    3-Fluoro-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   19.    8,8-Dimethyl-9[naphthalen-1-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   20.    9-[2-(4-Fluoro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   21.    9-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   22.    9-[2-(3,5-Dichloro-phenyl)-2-hydroxy-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   23.    9-[2-Benzo[1,3]dioxol-5-yl-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   24.    9-[2-(3-Bromo-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   25.    9-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   26.    3-Fluoro-9-(2-(S)-hydroxy-2-phenyl-ethyl)-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   27.    9-(2-Biphenyl-4-yl-2(S)-hydroxy-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   28.    9-[2-(3-Fluoro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   29.    9-(2(S)-Hydroxy-2-naphthalen-2-yl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   30.    9-[2-(4-Chloro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   31.    9-[2-(3,4-Dichlorophenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   32.    9-(2(S)-Hydroxy-2-p-tolyl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   33.    3-Bromo-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   34.    9-[2(S)-Hydroxy-2-(3-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   35.    9-[2-(2,4-Dichloro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   36.    3-Fluoro-9-(2(S)-hydroxy-2-phenyl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   37.    9-[2-(3-Methoxy-phenyl)-2oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   38.    9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one    (diastereoisomer I);-   39.    9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one    (diastereoisomer II);-   40. 8,8-dimethyl    9-(2-oxo-2-p-tolyl-ethyl)-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   41.    9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   42.    4-[2-(2,2-Dimethyl-6-oxo-8-pyridin-4-yl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-1-hydroxy-ethyl]-benzonitrile;-   43.    9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   44.    9-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   45.    9-[2-(4-Chloro-phenyl)-2-hydroxy-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   46.    9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   47.    9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;-   48.    8-Ethyl-9-(2-hydroxy-2-p-tolyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

As a further object, the present invention concerns also methods forpreparing the compounds represented by the aforementioned formula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Pyrimidone compounds represented by the aforementioned formula (I) maybe prepared according to scheme 1.

(In the above scheme the definition of R1, R2, R3, R4, R5, X, p, m and nare the same as those already described for compound of formula (I)).

The pyrimidone derivative represented by the above formula (III),wherein R1 is as defined for compound of formula (I), is allowed toreact with a base such as sodium hydride, sodium carbonate or potassiumcarbonate in a solvent such as N,N-dimethylformamide,N-methylpyrrolidone, N,N-dimethylacetamide or chloroform at a suitabletemperature ranging from 0 to 130° C. under ordinary air, then with acompound of formula (II), wherein R2, X, Y and n are as defined forcompound of formula (I) and L represents a leaving group preferablybromide or mesyl group, is added to obtain the compound of theaforementioned formula (I).

Compound of formula (II) are commercially available or may besynthesized according to well-known methods of one skilled in the art.The compound of formula (III) may be prepared according to the methoddefined in scheme 2.

(In the above scheme the definition of R1, R3, R4, R5, p and m are thesame as already described.)

According to this method, the 3-ketoester of formula (IV) is allowed toreact with a compound of formula (V). The reaction may be carried out inthe presence of potassium carbonate, in an alcoholic solvent such asmethanol, ethanol and the like or without, at a suitable temperatureranging from 250°–1400° C. under ordinary air.

Alternatively, compounds of formula (III) wherein R5 represents ahydrogen atom may be halogenated in order to give compounds of formula(III) wherein R5 is an halogen atom such as a bromine atom or a chlorineatom. The reaction may be carried out in an acidic medium such as aceticacid or propionic acid, in presence of bromosuccinimide orchlorosuccinimide, or bromine.

In addition, compounds of formula (III) wherein R5 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol.30, N^(o)45, pp 6113–6116, 1989.

Compounds of formula (V) or (IV) are commercially available or may besynthesized according to well-known methods of one skilled in the art.

For example compounds of formula (IV), wherein R1 represent a pyridinering optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group ora halogen atom, can be prepared by reacting a nicotinic acid optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or an halogen, witha malonic acid monoester. The reaction can be carried out using methodswell known to one skilled in the art, such as for example in presence ofa coupling agent such as 1,1′-carbonylbis-1H-imidazole in a solvent suchas tetrahydrofuran at a temperature ranging from 20 to 70° C.

Compounds of formula (I) may also be obtained starting from anothercompound of formula (I) using well-known methods of one skilled in theart.

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting group, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β or GSK3β and cdk5/p25 activity and more particularly ofneurodegenerative diseases such as Alzheimer's disease. In addition, thecompounds of the present invention are also useful as an activeingredient for the preparation of a medicament for preventive and/ortherapeutic treatment of neurodegenerative diseases such as Parkinson'sdisease, amyotrophic lateral sclerosis, tauopathies (e.g.frontotemporopadietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; smoking cessation and other withdrawalsyndromes, epilepsy; cancers such as breast cancer, non-small cell lungcarcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β or GSK3βand cdk5/p25 and of the aforementioned diseases which comprisesadministering to a mammalian organism in need thereof an effectiveamount of a compound of the formula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1 Compound N^(o) 8 of Table 19-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1) 1.17,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 5.9 g (30.55 mmol) of ethyl3-(pyridin-4-yl)-3-oxopropionate, 5.0 g (30.55 mmol) of5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride

(prepared by analogy to the method described in U.S. Pat. No. 4,262,122)and 6.33 g (45.82 mmol) of potassium carbonate in 60 ml of ethanol washeated at reflux temperature during 12 h. The cooled suspension wasfiltered and the solvent removed by evaporation. The residue obtainedwas dissolved in dichloromethane and washed with water. The organicphase was dried and evaporated to give 6.30 g (80%) of product as abeige solid. Mp.: 152–154° C.

1.2.9-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

A suspension of 0.8 g (3.12 mmol) of7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 8 ml of anhydrous dimethylformamide was treated with 274 mg (6.86mmol) of sodium hydride (60% suspension in mineral oil) and theresulting mixture was heated at 50° C. for 30 min. 0.494 ml (3.74 mmol)of (S)-2-chloro-1-phenylethanol was added and the reaction mixture washeated at 50° C. during 4 h.

The cooled solution was treated with water and extracted with ethylacetate. The organic phase was dried and evaporated to give crudeproduct, which was purified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 98/2 to 90/10. The 0.486 gof pure product obtained in the form of free base was dissolved in hotethanol and treated with 1 equivalent of hydrogen-chloride inisopropanol. The cooled solution was filtered to afford 0.192 g (15%) ofwhite solid. Mp: 234–236° C. [α]_(D)=−22.9° (c=1, CH₃OH)

Example 2 Compound N^(o)49 of Table 19-(2-Oxo-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one 2.15-Methyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride

To a solution containing 6.7 g (41.6 mmol) of 2-methyl-1,3-propandiaminehydrochloride (Tetrahedron (1994) 50(29), 8617–8632) in 50 ml ofmethanol was added 83 ml of a solution of sodium methylate in methanol(1 mmol/ml) and the resulting mixture treated with 3.97 g (41.6 mmol) ofguanidine hydrochloride. The reaction mixture was heated at 140° C. for3 h.

The solution was filtered, the solvent evaporated and the residueobtained was used directly in the next step.

2.27-Methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with step N^(o) 1.1 and using theintermediate from step N^(o) 2.1.

2.39-(2-Oxo-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.32 g (1.34 mmol) of7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 10 ml of anhydrous dimethylformamide was treated with 64 mg (1.34mmol) of sodium hydride (50% suspension in mineral oil) and theresulting mixture was stirred for 40 min. 0.267 g (1.34 mmol) ofphenacyl bromide was added and the reaction mixture stirred at roomtemperature for 2 h.

The solution was treated with water and extracted with ethyl acetate.The organic phase was dried and evaporated to give crude product, whichwas purified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 100/0 to 90/10 to give 0.235g of pure product obtained in the form of free base. Mp: 202–203° C.

Example 3 Compound N^(o) 47 of Table 19-[3-(2-Fluorophenyl)propyl]-7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one 3.17-Hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with step N^(o) 1.1 and using2-amino-1,4,5,6-tetrahydro-5-pyrimidinol (Arch.int.Pharmacodyn.Ther.(1968),175(1), 193–211). Mp.: 305–307° C.

3.29-[3-(2-Fluorophenyl)propyl]-7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 1.0 g (4.09 mmol) of7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-oneand 0.95 g (4.09 mmol) of1-[3-(methylsulfonyloxy)propyl]-2-fluorobenzene in 100 ml of anhydrousacetonitrile was treated with 4.1 g (1.42 mmol) of potassium fluoridesuspended on alumina (Fluka) and the resulting mixture was heated at 80°C. for 24 h.

The cooled solution was filtered and the solvent evaporated to leave aresidue, which was purified by silica gel chromatography, eluting withdichloromethane/methanol/ammonia in the proportions 98/2/0.2 to96/4/0.4. 0.96 g (61%) of pure product was obtained in the form of freebase. Mp: 205–207° C.

Example 4 Compound N^(o) 48 of Table 19-[3-(2-Fluorophenyl)propyl]-7-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-oneoxalate (1:1) 4.1 9-[3-(2Fluoraphenyl)propyl]-7-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-oneoxalate (1:1)

To a suspension containing 0.12 g (0.31 mmol) of9-[3(2-fluorophenyl)propyl]-7-hydroxy-2-(pyridin-4-yl)6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinonein 3 ml of dimethylformamide was added 14 mg (0.34 mmol) of a suspensionof sodium hydride in mineral oil (60%) and the resulting mixture wasstirred at room temperature for 15 min. The mixture was cooled to −20°C. and treated with 19.6 μL (0.31 mmol) of iodomethane. Stirring wascontinued for 1 h. Water was added and the organic phase was separated.The solvent was evaporated to leave a residue, which was purified bysilica gel chromatography, eluting with dichloromethane/methanol/ammoniain the proportions 98/2/0.2. 0.1 g (85%) of pure product was obtainedand transformed into a monooxalate salt by treatment with one equivalentof oxalic acid 0.085 g (65%). Mp: 164–166° C.

Example 5 Compound N^(o) 4 of Table 19-(2-Oxo-2-phenyl-ethyl)-7,7difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one5.1 5,5-Difluoro-1,4,5,6-tetrahydro-2-pyrimidinamine

The product was obtained by analogy with the method described in 2.1 andusing 2,2-difluoro-1,3-propandiamine (Tetrahedron (1994) 50(29),8617–8632) and was used as such in the next step.

5.27,7-Difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with step N^(o) 1.1 and using theintermediate from step N^(o) 5.2. Mp.: 239–240° C.

5.39-(2-Oxo-2-phenyl-ethyl)-7,7-difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 2.3 the compound wasobtained as a free base. Mp.: 217–219° C.

Example 6 Compound N^(o) 6 of Table 19-(2-Oxo-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1) 6.1 Ethyl 2-fluoro-3-oxo-3-pyridin-4-yl propanoatehydrochloride (cf. Tetrahedron Letters, Vol.30, N^(o) 45, pp 6113–6116,1989)

To a solution of 134.88 ml (0.54 mol) of tri-n-butylphosphine in 500 mlof anhydrous tetrahydrofuran under argon was added 63.8 ml (0.54 mol) ofethyl bromofluoroacetate and the resulting mixture stirred at roomtemperature during 40 h.

The reaction mixture was cooled to −78° C. and 237.58 ml (0.594 mol) ofn-butyl lithium (2.5M in hexane) was added dropwise and allowed to stirfor 1 h. 76.44 g (0.54 mol) of isonicotinoyl chloride (HeterocyclicChemistry, 18, 519, 1981) was added and the mixture allowed to stir for1 h. The temperature was allowed to increase to room temperature duringthe night and at 0° C., 700 ml of a 5% aqueous solution of sodiumbicarbonate was added and the resulting mixture allowed to stirovernight The tetrahydrofuran was evaporated under reduced pressure andthe resulting aqueous phase was extracted with dichloromethane, washedwith brine and dried over anhydrous sodium sulfate and evaporated togive a dark brown residue. Flash chromatography on silica gel (eluantcyclohexane/ethyl acetate 90/10 to 50/50). This product was treated witha solution of hydrochloric acid in isopropanol (6N) to give 20 g (17%)of product. Mp. 142–144° C.

6.27,7-Dimethyl-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 5.0 g (20.19 mmol) of ethylpyridin-4-yl-3-oxo-2-fluoropropanoate hydrochloride, 3.30 g (20.19 mmol)5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (preparedby analogy to the method described in U.S. Pat. No. 4,262,122 and 8.37 g(60.57 mmol) of potassium carbonate in 30 ml of ethanol were heated atreflux temperature during 18 h.

The cooled suspension was filtered and the solvent removed byevaporation. The residue obtained was treated with dichloromethane andwashed with water. The organic phase was dried and evaporated to give1.9 g (34%) of product as a beige solid. Mp.: 190–192° C.

6.39-(2-Oxo-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

A suspension of 0.30 g (1.09 mmol) of7,7-dimethyl-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 6 ml of anhydrous dimethylformamide was treated with 53 mg (1.31mmol) of sodium hydride (60% suspension in mineral oil) and theresulting mixture was stirred for 10 min. 0.261 g (1.31 mmol) ofphenacyl bromide was added and the reaction mixture stirred at roomtemperature for 3 h.

The solution was treated with water and extracted with ethyl acetate.The organic phase was dried and evaporated to give crude product, whichwas purified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 98/2 to 90/10 to give 0.10 gof pure product obtained in the form of free base which was transformedinto the hydrochloride salt. Mp: 236–238° C.

Example 7 Compound N^(o) 21 in Table 19-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one7.13-Bromo-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrobromide (1:1)

To a solution of 3.0 g (11.7 mmol) of7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 75 ml of acetic acid was added dropwise 0.6 ml (11.7 mmol) ofbromine. The mixture was allowed to stir at room temperature for 2 h.

The precipitated solid was recovered by filtration, washed with etherand dried affording 4.53 g (97%) of product as a yellow solid. Mp.:270–272° C.

9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A solution containing 4.15 g (10.43 mmol) of3-bromo-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrobromide in water was treated with an excess of an aqueous solutionof sodium hydroxide. The free base was extracted with dichloromethaneand the organics dried and evaporated. The residue was solubilized in 25ml of anhydrous dimethylformamide and 0.542 g (13.56 mmol) of sodiumhydride (60% suspension in mineral oil) and the resulting mixture wasstirred for 40 min. 2.43 g (12.49 mmol) of phenacyl bromide was addedand the reaction mixture stirred at room temperature for 5 h.

The solution was treated with water at 0° C. and the precipitate whichformed was recovered by filtration and dried, 3.5 g (74%). Mp: 223–225°C.

Example 8 Compound N^(o) 38 in Table 19-(2-Oxo-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one8.13-Methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 14.0 g (67.56 mmol) of ethyl2-methyl-3-(pyridin-4-yl)-3-oxopropionate (prepared by analogy to themethod described in French Patent FR 2529786), 9.16 g (67.66 mmol) of1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (preparedaccording to J. Org. Chem. 1955, 20, 829) and 9.33 g (67.66 mmol) ofpotassium carbonate in 300 ml of ethanol was heated at refluxtemperature during 12 h.

The cooled suspension was filtered and the solvent removed byevaporation. The residue obtained was treated with water and theprecipitate filtered and dried. The product was thus obtained as a brownsolid. 10.5 g (64%) Mp.: 242–243° C.

8.29-(2-Oxo-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.25 g (1.03 mmol) of3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 4 ml of anhydrous dimethylformamide was treated with 45 mg (1.03mmol) of sodium hydride (50% suspension in mineral oil) and theresulting mixture was stirred for 1 h. 0.205 g (1.03 mmol) of phenacylbromide was added and the reaction mixture stirred at room temperaturefor 5 h.

The solution was treated with water and extracted with ethyl acetate.The organic phase was dried and evaporated to give crude product, whichwas purified by silica gel chromatography, eluting withdichloromethane/methanol/ammonia in the proportions 98/2/0.2 to give0.10 g (27%) of pure product obtained in the form of free base. Mp:190–192° C.

Example 9 Compound N^(o) 2 in Table 19-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride(1:1)

The product was obtained by using the method described in step 2.3 andemploying 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one. Mp.: 283–285° C.

Example 10 Compound N^(o) 3 in Table 1 9-(2-Hydroxy-2-phenyl-ethyl)-7,7dimethyl-2(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

To a solution of 2.0 g (5.34 mmol) of9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-2-((pyridin-4-yl))-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-oneobtained in step 9 in 100 ml of methanol at 0° C. was added 0.24 g (6.41mmol) of sodium borohydride. Stirring was maintained for 30 min. and thesolvent was removed by evaporation.

Water was added and the resulting mixture extracted withdichloromethane. The organics were dried and evaporated and the residuewas triturated with ethyl acetate to give 1.66 g (83%) of product. TheZ-but-2-endioate salt of the product was characterized. Mp.: 195–197° C.

Example 11 Compound N^(o) 34 in Table 19-(2-Amino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1) 11.12-[2-(3,3-Dimethyl-6-oxo-8-(pyridin-4-yl)-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-1-phenyl-ethyl]-isoindole-1,3-dione

To a solution of 0.2 g (0.531 mmol) of9-(2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one,0.080 g (0.584 mmol) of phthalimide and 0.195 g (0.742 mmol) in 30 ml ofanhydrous tetrahydrofuran at 0° C. was added 0.142 ml (0.903 mmol) ofdiethyl azodicarboxylate and the reaction mixture stirred for 18 h.

The solvent was evaporated and the residue was purified bychromatography on silica gel eluting withdichloromethane/methanol/diethylamine in the proportions 98/2/0.2 togive 0.06 g (22%) of product.

11.29-(2-Amino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

A solution of 0.470 g (0.929 mmol) of2-[2-(3,3-dimethyl-6-oxo-8-(pyridin-4-yl)-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-1-phenyl-ethyl]-isoindole-1,3-dionein 50 ml of ethanol containing 0.452 ml (9.29 mmol) of hydrazine hydratewas heated at reflux temperature for 18 hr.

The cooled solution was filtered and the solvent removed by evaporation.The residue was purified by chromatography on silica gel eluting withethyl acetate/methanol/diethylamine in the proportions 95/5/0.5 to94/6/0.6. The free base recovered was transformed into the hydrochloridesalt to give 0.283 g (68%) of product. Mp.: 227–231° C.

Example 12 Compound N^(o) 1 in Table 2[3-(2-Fluoro-phenyl)-propyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-onehydrochloride (1:2) 12.1 5,5-Dimethyl-4,5-dihydro-1H-imidazol-2-ylaminehydrobromide (1:1)

To a solution of 15 g (0.17 mol) of 1,2-diamino-2-methylpropane in 150ml of water at 0° C., was added 18 g (0.17 mol) of cyanogen bromideportionwise and the temperature was allowed to warm to room temperatureduring 4 h. The water was removed by evaporation and ethanol was addedand evaporated. Trituration in a mixture of diethyl ether and ethanolgave 29.5 g (89%) of product as an amorphous hygroscopic solid.

12.22,2-Dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

A suspension of 4.5 g (23.2 mmol) of5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide, 2.99 g(15.46 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate and 4.27 g (30.89mmol) of potassium carbonate in 100 ml of ethanol was heated at refluxtemperature for 18 h.

The cooled suspension was filtered and the solvents evaporated. Theresidue obtained was dissolved in dichloromethane and washed with water.The solvent was evaporated to give 2.5 g (67%) of pure product. Mp.:226–228° C.

12.3[3-(2-Fluoro-phenyl)-propyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-onehydrochloride (1:2)

A suspension of 0.3 g (1.23 mmol) of2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-onein 6 ml of anhydrous dimethylformamide was treated with 64 mg (1.6 mmol)of sodium hydride (60% suspension in mineral oil) The mixture was heatedat 60° C. for 10 min. and then 0.322 g (1.48 mmol) of3-(2-fluorophenyl)propyl bromide was added and the mixture heated at120° C. during 1 h.

The cooled solution was treated with water and extracted with ethylacetate. The solvent was evaporated to leave a residue which waspurified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 98/2 to 95/5 to obtain 0.248g (55%) of pure product was obtained in the form of free base which wastransformed into the dihydrochloride salt Mp: 140–142° C.

Example 13 Compound No. 1 of Table 39-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one13.18-Methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 6 g (31.0 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate,4.6 g (31.0 mmol) 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylaminehydrochloride (prepared according to J. Org. Chem., 20, 1955, 829–838)and 6.44 g (46.0 mmol) of potassium carbonate in 50 ml of ethanol wereheated at reflux temperature during 18 h.

The reaction mixture was cooled and the solvent removed by evaporation.The residue obtained was treated with water and the precipitaterecovered by filtration to give 3.85 g (51%) of product. Mp.: 245–247°C.

13.2 (4-Fluoro-2-methoxy-phenyl)-acetic acid methyl ester

To a suspension of 14.34 g (32.47 mmol) of lead (IV) acetate in 100 mlof anhydrous toluene was added a mixture of 5.2 g (30.92 mmol) of1-(4fluoro-2-methoxy-phenyl)-ethanone and 15.02 ml (123.13 mmol) ofboron trifluoride etherate in 9 ml of methanol. The reaction mixture isfurther stirred at room temperature for 16 h. Water was added to thecooled mixture and the resulting solution extracted with toluene. Theextracts were washed with saturated sodium hydrogen carbonate solution,saturated sodium chloride solution and dried with sodium sulphate. Thesolvent was evaporated to dryness to give 6 g of product as an oil,which was used in the subsequent step without further purification.

13.3 2-(4-Fluoro-2-methoxy-phenyl)-ethanol

To a suspension of 1.72 g (45.41 mmol) of lithium aluminum hydride in120 ml of tetrahydrofuran at 0° C. was added dropwise 6 g (30.27 mmol)of dissolved in 120 ml of (4-Fluoro-2-methoxy-phenyl)-acetic acid methylester and the resulting mixture stirred at room temperature for 1 h.

The reaction mixture was diluted with 100 ml of diethylether at 0° C.and treated with excess of a saturated aqueous solution of sodiumsulfate. Further solid sodium sulfate was added and the organic phasewas filtered to remove salts. The solvent was evaporated to dryness togive 5.1 g (99%) of product as an oil.

13.4 Methanesulfonic acid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester

To a solution of 5.1 g (29.97 mmol) of2-(4-Fluoro-2-methoxy-phenyl)-ethanol in 30 ml of anhydrousdichloromethane was added at 0° C. 6.26 ml (44.95 mmol) of triethylamineand 3.5 ml (44.95 mmol) of methanesulfonyl chloride. The resultingmixture was stirred at 0° C. for 1 h. The mixture was then diluted withwater and dichloromethane and extracted with dichloromethane. Organiclayer was dried and evaporated to give 7 g(100%) of methanesulfonic acid2-(4-fluoro-2-methoxy-phenyl)-ethyl ester.

13.59-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

To a solution of 0.25 g (1.03 mmol) of8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 4 ml of anhydrous dimethylformamide was added 0.046 mg (1.14 mmol) ofsodium hydride (60% suspension in mineral oil) and the mixture allowedto stir at 50° C. for 20 min. 0.282 g (1.14 mmol) of methanesulfonicacid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester was added and stirringcontinued for 18 h.

Water was added and the mixture extracted with dichloromethane. Theextracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to give crude product. Purification bychromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 96/4. The compoundwas obtained in the form of free base which was transformed into itshydrochloride salt to give 0.192 g (43%) of pure product. Mp.: 206–208°C.

Example 14 Compound No. 2 in Table 39-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one14.18,8-Dimethyl-2-(pyridinyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 7.68 g (39.8 mmol) of ethyl3-(pyridin-4-yl)-3-oxopropionate, 7.9 g (37.9 mmol)6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide(prepared according to Bull. Soc. Chim. Belg., 1950, 59, 573–587) and 11g (79.5 mmol) of potassium carbonate in 80 ml of ethanol were heated atreflux temperature during 18 h.

The reaction mixture was cooled and the solvent removed by evaporation.The residue obtained was treated with water and the precipitaterecovered by filtration to give 3.21 g (33%) of product. Mp.: 345–347°C.

14.29-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

To a solution of 0.222 g (0.87 mmol) of8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 5 ml of anhydrous dimethylformamide was added 0.039 g (0.95 mmol) ofsodium hydride (60% suspension in mineral oil) and the mixture allowedto stir at 50° C. for 20 min. 0.236 g (0.95 mmol) of methanesulfonicacid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester was added and stirringcontinued for 18 h.

Water was added and the mixture extracted with dichloromethane. Theextracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to give crude product. Purification bychromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 96/4 gave 0.18 g(50%) of pure product. Mp.: 217–219° C.

Example 15 Compound No. 8 in Table 39-(2(S)-Hydroxy-2-phenyl-ethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

To a solution of 1 g (3.90 mmol) of8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 12 ml of anhydrous dimethylformamide was added 0.343 g (8.58 mmol) ofsodium hydride (60% suspension in mineral oil) and the mixture allowedto stir at 50° C. for 1 h. 0.794 g (5.07 mmol) of(1-S)-2-chloro-1-phenyl ethanol was added and the mixture allowed tostir at 120° C. for 12 h.

Water was added and the mixture extracted with ethyl acetate. Theextracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to give crude product. Purification bychromatography on silica gel eluting with a mixture of ethylacetate/ethanol in the proportions 100/0 to 96/4. The compound wasobtained in the form of free base which was transformed into itshydrochloride salt to give 0.87 g (59%) of pure product. Mp: 204–206°C., [α]_(D)=−20.70 (c=0.855, CH₃OH).

Example 16 Compound No. 10 in Table 38,8-Dimethyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1).

To a solution of 0.12 ml (1.65 mmol) of dimethyl sulphoxide in 3 ml ofanhydrous dichloromethane at −78° C. was added 0.21 ml (1.46 mmol) oftrifluoroacetic anhydride in 1 ml of anhydrous dichloromethane and themixture allowed to stir at −78° C. for 20 min. 0.1 g (0.27 mmol) of9-(2(S)-hydroxy-2-phenyl-ethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 2 ml of anhydrous dichloromethane was added at −78° C. and stirringcontinued for 30 min.

0.31 ml (2.23 mmol) of triethylamine was added and the mixture allowedto stir at room temperature for 12 h. Water was added and the mixtureextracted with ethyl acetate, the extracts were washed with a saturatedaqueous solution of ammonium chloride, a saturated aqueous solution ofsodium chloride, dried and evaporated to give crude product.Purification by chromatography on silica gel eluting with a mixture ofdichloromethane/methanol/ammonium hydroxide in the proportions 95/5/0.5.The compound was obtained in the form of free base which was transformedinto its hydrochloride salt to give 0.026 g (24%) of pure product. Mp:247–249° C.

Example 17 Compound No. 16 in Table 38-Ethyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1). 17.18-Ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 5 g (25.88 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate,3.85 g (23.53 mmol) of 6-ethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylaminehydrochloride (prepared according to J. Org. Chem., 20, 1955, 829–838)and 6.83 g (49.41 mmol) of potassium carbonate in 51 ml of ethanol wereheated at reflux temperature during 18 h.

The reaction mixture was cooled and the solvent removed by evaporation.The residue obtained was treated with water and the precipitaterecovered by filtration to give 4.1 g (68%) of product. Mp.: 244–246° C.

17.28-Ethyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1).

To a solution of 0.3 g (1.17 mmol) of8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 6 ml of anhydrous dimethylformamide was added 0.343 g (8.58 mmol) ofsodium hydride (60% suspension in mineral oil) and the mixture allowedto stir at 50° C. for 15 min. At 0° C., 0.303 g (1.52 mmol) of phenacylbromide was added the mixture allowed to stir at 0  C. for 3 h and thetemperature was allowed to warm to room temperature during 12 h.

Water was added and the mixture extracted with ethyl acetate. Theextracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to give crude product. Purification bychromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 96/4. The compoundwas obtained in the form of free base which was transformed into itshydrochloride salt to give 0.134 g (28%) of pure product. Mp: 189–191°C.

Example 18 Compound No. 18 in Table 33-Fluoro-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.18.13-Fluoro-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

The product was obtained by analogy with step N^(o) 13.1 and using theintermediate from step N^(o) 6.1. Mp.: 274–276° C.

18.23-Fluoro-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

The product was obtained by analogy with step N^(o) 17.2. Mp.: 201–202°C.

A list of chemical structures and physical data for compounds of theaforementioned formula (I) illustrating the present invention is givenin tables 1 and 2. The compounds have been prepared according to themethods of the example.

In the tables, R1 is an unsubstituted 4-pyridine ring (4-py), Phrepresents a phenyl group, Et represents an ethyl group, Me represents amethyl group; in the column “X”, when X represents two hydrogen atoms,only “H” is indicated, (S), (R) or (Rac.) indicates in the column “Y”the stereochemistry respectively, (S), (R) or (Rac.) of the carbon atom.

(rac.) means racemic mixture

(R) means absolute R configuration

(S) means absolute S configuration

In table 1, for compounds of formula (I) “m” and “p” equal 1; in table2, for compounds of formula (I), “m” equals 0 and “p”) equals 1 and intable 3 for compounds of formula (I) “m” equals 0 and “p” equals 2.

TABLE 1 (I)

N° X Y R2 R3 R4 R5 n Mp ° C. salt 1 H CH₂

CH₃ CH₃ H 1 250–252 (1:1)hydro-chloride 2 H CO Ph CH₃ CH₃ H 0 283–255(1:1)hydro-chloride 3 H CH(OH)(rac.) Ph CH₃ CH₃ H 0 195–197(1:1)(Z)-but-2-enedioate 4 H CO Ph F F H 0 217–219 Free base 5 H CH(OH)Ph F F H 0 179–180 Free base (S) 6 H CO Ph CH₃ CH₃ F 0 236–238(1:1)hydro-chloride 7 H CO

CH₃ CH₃ H 0 238–240 (1:1)hydro-chloride 8 H CH(OH) Ph CH₃ CH₃ H 0234–236 (1:1)hydro- (S) chloride 9 H CO

CH₃ CH₃ H 0 233–235 (1:1)hydro-chloride 10 H CH(OH)(rac.)

CH₃ CH₃ H 0 195–197 Free base 11 H CH(OH)(rac.)

CH₃ CH₃ H 0 198–199 Free base 12 H CH(OH) Ph CH₃ CH₃ F 0 228–230(1:1)hydro- (S) chloride 13 H CO

CH₃ CH₃ H 0 256–257 (1:1)hydro-chloride 14 H CO

CH₃ CH₃ H 0 237–238 (1:1)hydro-chloride 15 H CO

CH₃ CH₃ H 0 203–204 (1:1)hydro-chloride 16 H CO

CH₃ CH₃ H 0 232–233 (1:1)hydro-chloride 17 H,CH₃(rac.) CO

CH₃ CH₃ H 0 241–242 (1:1)hydro-chloride 18 H CO

CH₃ CH₃ H 0 257–258 (1:1)hydro-chloride 19 H CO

CH₃ CH₃ H 0 232–233 (1:1)hydro-chloride 20 H CO

CH₃ CH₃ H 0 256–257 (1:1)hydro-chloride 21 H CO Ph CH₃ CH₃ Br 0 223–225Free base 22 H CH(OMe) Ph CH₃ CH₃ H 0 145–146 Free base (S) 23 O CH₂ PhCH₃ CH₃ H 1 134–136 Free base 24 H C(OH)(CH₃) Ph CH₃ CH₃ H 0 208–210Free base (rac.) 25 O C(OMe)(CF₃) Ph CH₃ CH₃ H 0 162–163 Free base(rac.) 26 H C(OH)(Ph) Ph CH₃ CH₃ H 0 270–272 Free base (rac.) 27 H

Ph CH₃ CH₃ H 0 249–250 Freebase 28 H C(OH)(CH₃) Ph CH₃ CH₃ F 0 230–232(1:1)hydro- (rac.) chloride 29 H

Ph CH₃ CH₃ H 0 214–215 Free base 30 H CH(OH) CH₂OH CH₃ CH₃ H 0 242–243(1:1)hydro- (rac.) chloride 31 H C(H)(OMe) Ph CH₃ CH₃ H 0 190–192(1:1)hydro- (R) chloride 32 H C(H)(OH)(rac.)

CH₃ CH₃ H 0 199–200 Free base 33 H C(H)(NHAc) Ph CH₃ CH₃ H 0 246–247Free base (rac.) 34 H C(H)(NH₂) Ph CH₃ CH₃ H 0 227–231 (1:1)hydro-(rac.) chloride 35 H C(H)(OH)(rac.)

CH₃ CH₃ H 0 156–157 Free base 36 H CO Ph H H F 0 264–266 (1:1)hydro-chloride 37 H CO

H H F 0 260–262 (1:1)hydro-chloride 38 H CO Ph H H CH₃ 0 190–192 Freebase 39 H CO Ph H H Cl 0 260–262 (1:1)hydro- chloride 40 H CO Ph H H Br0 260–262 (1:1)hydro- chloride 41 H CO

H H CH₃ 0 242–243 Free base 42 H C(H)(OH) Ph H H Cl 0 221–213(1:1)hydro- (S) chloride 43 H C(H)(OH) Ph H H CH₃ 0 211–213 (1:1)hydro-(S) chloride 44 H C(H)(OH) Ph H H F 0 170–172 (1:1)hydro- (S) chloride45 H C(H)(OMe) Ph H H F 0 108–110 (1:1)hydro- (S) chloride 46 HC(H)(OMe) Ph H H F 0 202–204 (1:1)hydro- (R) chloride 47 H CH₂

H OH(rac) H 1 205–207 Free base 48 H CH₂

H OMe(rac) H 1 164–166 (1:1)oxalate 49 H CO Ph H CH₃ H 0 202–203 Freebase (rac) 50 H C(H)(OH) Ph H CH₃ H 0 174–175 Free base (rac.) (rac) 51H C(OH)(CH₃) Ph CH₃ CH₃ H 0 150–151 Free base chiral 52 H C(OH)(CH₃) PhCH₃ CH₃ H 0 144–146 Free base chiral 53 H C(H)(OMe) Ph CH₃ CH₃ H 0143–145 Free base (R) 54 H CH₂

H H F 0 190–192 Free base 55 H bond

CH₃ CH₃ H 0 238–240 (1:1)hydrochloride 56 H CH₂

CH₃ CH₃ F 0 140–142 Free base 57 H CH₂

CH₃ CH₃ H 0 235–237 (1:1)hydrochloride

TABLE 2

N° X Y R2 R3 R4 R5 n Mp ° C. Salt 1 H CH₂

CH₃ CH₃ H 1 140–142 (1:1)hydrochloride 2 H CO Ph CH₃ CH₃ H 0 314–416(1:1)hydrochloride 3 H C(H)(OH) Ph CH₃ CH₃ H 0 173–175 base (rac.) 4 HCO

CH₃ CH₃ H 0 268–269 (1:1)hydrochloride 5 H CO

CH₃ CH₃ H 0 252–253 (1:1)hydrochloride 6 H CO

CH₃ CH₃ H 0 230–231 (1:1)hydrochloride 7 H,CH₃(rac.) CO

CH₃ CH₃ H 0 259–260 (1:1)hydrochloride 8 H CO

CH₃ CH₃ H 0 186–187 (1:1)hydrochloride 9 H CO

CH₃ CH₃ H 0 249 (1:1)hydrochloride 10 H CO

CH₃ CH₃ H 0 233 (1:1)hydrochloride 11 H CO

CH₃ CH₃ H 0 250–251 (1:1)hydrochloride

TABLE 3 (I)

N° X Y R2 R3 R4 R5 n Mp ° C. salt 1 H CH₂

CH₃(Rac.) H H 0 206–208 Hydro-chloride(1:1) 2 H CH₂

CH₃ CH₃ H 0 217–219 Free base 3 H CH₂

CH₃(Rac.) H H 0 230–232 Hydro-chloride(1:1) 4 H CO Ph CH₃ H H 0 279–291Hydro- chloride (1:1) 5 H CH₂

CH₃(Rac.) H H 0 136–138 Hydro-chloride(1:1) 6 H CH₂

CH₃(Rac.) H H 0 236–238 Hydro-chloride(1:1) 7 H C(H)(OH) Ph CH₃ H H 0105–107 Free base (S) (Rac.) 8 H C(H)(OH) Ph CH₃ CH₃ H 0 204–206 Hydro-(S) chloride (1:1) 9 H bond

CH₃(Rac.) H H 0 275–277 Hydro-chloride(1:1) 10 H CO Ph CH₃ CH₃ H 0247–249 Hydro- chloride (1:1) 11 H bond

CH₃(Rac.) H H 0 210–212 Hydro-chloride(1:1) 12 H CO

CH₃(Rac.) H H 0 260–262 Hydro-chloride(1:1) 13 H CO

CH₃(Rac.) H H 0 258–260 Hydro-chroride(1:1) 14 H C(H)(CH₃) Ph CH₃ CH₃ H0 165–167 Hydro- (S) chloride (1:1) 15 H C(H)(CH₃) Ph CH₃ CH₃ H 0158–160 Hydro- (R) chloride (1:1) 16 H CO Ph CH₃CH₂ H H 0 189–191 Hydro-(Rac.) chloride (1:1) 17 H C(H)(OH) Ph CH₃CH₂ H H 0 176–180 Hydro- (S)(Rac.) chloride (1:1) 18 H CO Ph CH₃ H F 0 201–202 Free base (Rac.) 19 Hbond

CH₃ CH₃ H 0 178–180 Hydro-chloride(1:1) 20 H C(H)(OH)(S)

CH₃ CH₃ H 0 198–200 Free base 21 H C(H)(OH)(Rac.)

CH₃(Rac.) H H 0 232–234 Hydro-chloride(1:1) 22 H C(H)(OH)(Rac.)

CH₃(Rac.) H H 0 251–253 Hydro-chloride(1:1) 23 H CO

CH₃(Rac.) H H 0 233–235 Hydro-chloride(1:1) 24 H C(H)(OH)(S)

CH₃ CH₃ H 0 244–246 Hydro-chloride(1:1) 25 H CO

CH₃(Rac.) H H 0 262–264 Hydro-chloride(1:1) 26 H C(H)(OH) Ph CH₃ H F 0170–172 Free base (S) (Rac.) 27 H C(H)(OH)(S)

CH₃ CH₃ H 0 188–190 Hydro-chloride(1:1) 28 H C(H)(OH)(S)

CH₃ CH₃ H 0 217–219 Hydro-chloride(1:1) 29 H C(H)(OH)(S)

CH₃ CH₃ H 0 231–233 Hydro-chloride(1:1) 30 H C(H)(OH)(S)

CH₃ CH₃ H 0 209–211 Hydro-chloride(1:1) 31 H C(H)(OH)(S)

CH₃ CH₃ H 0 257–259 Hydro-chloride(1:1) 32 H C(H)(OH)(S)

CH₃ CH₃ H 0 193–195 Hydro-chloride(1:1) 33 H CO Ph CH₃ H Br 0 288–290Free base (Rac.) 34 H C(H)(OH)(S)

CH₃ CH₃ H 0 111–113 Free base 35 H C(H)(OH)(S)

CH₃ CH₃ H 0 241–243 Hydro-chloride(1:1) 36 H C(H)(OH) Ph CH₃ CH₃ F 0231–233 Hydro- (S) chloride (1:1) 37 H CO

CH₃ CH₃ H 0 182–184 Free base 38 H C(H)(OH)(S) Ph CH₃ H H 0 165–167(Dia.I) Free base 39 H C(H)(OH) Ph H CH₃ H 0 118–120 Free base (S) (Dia. II)40 H CO

CH3 CH3 H 0 204–206 Free base 41 H CO

CH₃ CH₃ H 0 162–184 Free base 42 H C(H)(OH)(S)

CH₃ CH₃ H 0 241–243 Hydro-chloride(1:1) 43 H CO

CH₃ CH₃ H 0 196–198 Hydro-chloride(1:1) 44 H C(H)(OH)(S)

CH₃ CH₃ H 0 237–239 Hydro-chloride(1:1) 45 H C(H)(OH)(S)

Et(Rac) H H 0 172–174 Free base 46 H CO

Et(Rac) H H 0 222–224 Hydro-chloride(1:1) 47 H CO

Et(Rac) H H 0 172–174 Hydro-chloride(1:1) 48 H C(H)(OH)(S)

Et(Rac) H H 0 208–210 Hydro-chloride(1:1)

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3β (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3β.

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:NH2-YRRMVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 is between 4 nanomolar to 2 micromolarconcentrations, of the compounds in table 2 is between 30 nanomolar to 2micromolar concentrations and of the compounds in table three is between1 nanomolar to 2 micromolar.

Test Example 2 Inhibitory Activity of the Medicament of the PresentInvention Against cdk5/p25

The following protocol may be used:

0.4 mg/ml Histone H1 and 10 μM ATP (containing 300,000 cpm of ³³P-ATP)were incubated in 50 mM Hepes, pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA,0.02% Tween 20 buffer for 1 hour at room temperature in the presence ofcdk5/p25 (total reaction volume: 100 microliters).

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml (dilutedto 1:100 before use). An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The cdk5/p25 inhibitory activity of the compounds of the presentinvention are expressed as IC₅₀ values. Typically, 3-fold serialdilutions of the inhibitor over at least a 1000-fold concentration rangeare used.

As an illustration the range of IC₅₀'s of the compounds in table 1 isbetween 200 nanomolar to 5 micromolar concentrations.

As an illustration the specific IC₅₀'s of some compounds of theaforementioned formula (I) illustrating the present invention are givenin table 4.

TABLE 4 Table No. Compound No. TPK1 IC50 μM TPK2 IC50 μM 1 37 0.004 4.63 32 0.001 >1.0 1 45 0.006 >1.0 3 7 0.004 0.344 1 12 0.011 0.334 1 390.004 0.062 1 5 0.060 0.067 1 40 0.005 0.077 1 42 0.028 0.154 1 44 0.006>1.0

Formulation Example (1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1  30 mg Olive oil 300 mg Lecithin  20 mg

(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β or GSK3β and cdk5/p25inhibitory activity and are useful as an active ingredient of amedicament for preventive and/or therapeutic treatment of diseasescaused by abnormal activity of GSK3β or GSK3β and cdk5/p25 and moreparticularly of neurodegenerative diseases.

1. A compound of formula (I) or a salt thereof;

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, anethenylene group, an ethynylene group, an oxygen atom, a sulfur atom, asulfonyl group, a sulfoxide group, a carbonyl group, ahydroxyiminomethylene group, a dioxolan group, a nitrogen atom beingoptionally substituted by a C₁₋₆ alkyl group, a phenyl group or a benzylgroup; or a methylene group optionally substituted by one or two groupschosen from a C₁₋₆ alkyl group, a benzyl group, a hydroxyl group, a C₁₋₄alkoxy group, a C₁₋₂ perhalogenated alkyl group, an amino group, anacetylamino group or a phenyl group; R1 represents a 2, 3 or 4-pyridinering optionally substituted by a C₃₋₆ cycloalkyl group, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a benzyl group or a halogen atom; when Yrepresents a bond, a methylene group optionally substituted, ahydroxyiminomethylene group, a dioxolan group or a carbonyl group thenR2 represents a C₁₋₆ alkyl group optionally substituted by a hydroxygroup, a C_(6,10) aryloxy or a C_(6,10) arylamino group; a C₃₋₆cycloalkyl group, a C₁₋₄ alkylthio group, a C₁₋₄ alkoxy group, a C₁₋₂perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, a phenylthiogroup, a benzyl group, a benzene ring, an indan ring, a5,6,7,8-tetrahydronaphthalene ring, a naphthalene ring, a pyridine ring,a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring; thebenzyl group or the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylendioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, C₁₋₄ alkylsulfonyloxy group or a phenyl group; whenY represents a ethenylene group, a ethynylene group, an oxygen atom, asulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atombeing optionally substituted then R2 represents a C₁₋₆ alkyl groupoptionally substituted by a hydroxy group, a C_(6,10) aryloxy or aC_(6,10) arylamino group; a C₃₋₆ cycloalkyl group, a C₁₋₂ perhalogenatedalkyl group, a C₁₋₃ halogenated alkyl group, a benzyl group, a benzenering, an indan ring, a 5,6,7,8-tetrahydronaphthalene ring, a naphthalenering, a C_(6,10) arylamino, a pyridine ring, a pyrrole ring, a thiophenering, a furan ring or an imidazole ring ; the benzyl group or the ringsbeing optionally substituted by 1 to 4 substituents selected from a C₁₋₆alkyl group, a methylendioxy group, a halogen atom, a C₁₋₂perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, a hydroxylgroup, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, a C₁₋₅monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, C₁₋₄ alkylsulfonyloxy group or a phenyl group; R3represents a hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄alkoxy group or a halogen atom; R4 represents a hydrogen atom, a C₁₋₆alkyl group, a hydroxy group, a C₁₋₄ alkoxy group or a halogen atom; R5represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; withthe proviso that when R3 and R4 represent each a hydrogen atom then R5is not a hydrogen atom; when m equals 0, p equals 1, 2 or 3, when mequals 1, p equals 0, 1 or 2, when m equals 2, p equals 0 or 1; and nrepresents 0 to
 3. 2. The compound according to claim 1 , wherein R1represents an unsubstituted pyridine ring.
 3. A pyrimidone derivativewhich is selected from the group consisting of:9-[3-(2-Fluorophenyl)-propyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-7,7-difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(3-chlorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(3-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Hydroxy-2-(3-chlorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Hydroxy-2-(3-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-fluoro-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(4-fluorophenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(3-methoxyphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(4-phenylphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-(1-Methyl-2-oxo-2-(3,4-methylendioxy-5-methoxyphenyl)-ethyl)]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(4-chlorophenyl)ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(naphth-2-yl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(4-methylphenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-7,7-dimethyl-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(3-Phenyl-propanoyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Methoxy-2-phenyl-2-trifluoromethyl-ethanoyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2,2-diphenylethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxyimino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one7,7-Dimethyl-9-(2-phenyl-[1,3]dioxolan-2-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2,3-Dihydroxypropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(2(R)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-3-phenylaminopropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Acetylamino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Amino-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-3-phenoxypropyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[2-Oxo-2-(3-fluorophenyl)-ethyl]-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-3-chloro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-3-bromo-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one2-(7-Methyl-6-oxo-8-pyridinyl-3,4-dihydro-2H, 6Hpyrimido[1,2-a]pyrimidin-1-yl)-N-phenyl-acetamide9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-chloro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Methoxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(R)-Methoxy-2-phenyl-ethyl)-3-fluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-[3-(2-Fluorophenyl)propyl]-7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one9-[3-(2-Fluorophenyl)propyl]-7-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Oxo-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-phenyl-ethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2-Hydroxy-2-methyl-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-(2(R)-Methoxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one3-Fluoro-9-[2-(4-fluoro-2-methoxy-phenyl)-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one9-Indan-2-ylmethyl-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one3-Fluoro-9-[2-(4-fluoro-2-methoxy-phenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;and9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;or a salt thereof.
 4. A pyrimidone derivative which is selected from thegroup consisting of:[3-(2-Fluoro-phenyl)-propyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-phenylethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Hydroxy-2-phenylethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-(4-chlorophenyl)ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-(4-methylphenyl)ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-4-phenylphenyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[1-Methyl-2-oxo-2-(3,4-methylendioxy-5-methoxyphenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-(naphth-2-yl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-(4-fluorophenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one[2-Oxo-2-(3-methoxyphenyl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;and[2-Oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-ethyl]-2,2-dimethyl-7-(pyridin-4-yl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;or a salt thereof.
 5. A pyrimidone derivative which is selected from thegroup consisting of:9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(4-Fluoro-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8-Methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(2,5-Dimethoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(2-methoxy-phenyl)-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2(S)-Hydroxy-2-phenyl-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8-Methyl-9-[naphthalen-1-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8,8-Dimethyl-9-[2-oxo-2-phenyl-ethyl]-2(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8-Methyl-9-[naphthalen-2-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8,8-Dimethyl-9-[2(S)-phenyl-propyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8,8-Dimethyl-9-[2(R)-phenyl-propyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8-Ethyl-9-[2-oxo-2-phenyl-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8-Ethyl-9-[2(S)-hydroxy-2-phenyl-ethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one3-Fluoro-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8,8-Dimethyl-9[naphthalen-1-ylmethyl]-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(4-Fluoro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3,5-Dichloro-phenyl)-2-hydroxy-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-Benzo[1,3]dioxol-5-yl-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3-Bromo-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one3-Fluoro-9-(2-(S)-hydroxy-2-phenyl-ethyl)-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-(2-Biphenyl-4-yl-2(S)-hydroxy-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3-Fluoro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-naphthalen-2-yl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(4-Chloro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(3,4-Dichlorophenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-(2(S)-Hydroxy-2-p-tolyl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one3-Bromo-8-methyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2(S)-Hydroxy-2-(3-methoxy-phenyl)-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9-[2-(2,4-Dichloro-phenyl)-2(S)-hydroxy-ethyl]-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one3-Fluoro-9-(2(S)-hydroxy-2-phenyl-ethyl)-8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(diastereoisomer I);9-[2(S)-Hydroxy-2-phenyl-ethyl]-8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(diastereoisomer II); 8,8-dimethyl9-(2-oxo-2-p-tolyl-ethyl)-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;4-[2-(2,2-Dimethyl-6-oxo-8-pyridin-4-yl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-1-hydroxy-ethyl]-benzonitrile;9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-Chloro-phenyl)-2-hydroxy-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-ethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;and8-Ethyl-9-(2-hydroxy-2-p-tolyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-oneor a salt thereof.
 6. A method for treatment non-insulin dependentdiabetes; which comprises administering to a patient in need of saidtreatment an effective amount of a compound according to claim
 1. 7. Amethod for treatment of non-insulin dependent diabetes; which comprisesadministering to a patient in need of said treatment an effective amountof a compound according to claim
 2. 8. A method for treatment ofnon-insulin dependent diabetes; which comprises administering to apatient in need of said treatment an effective amount of a compoundaccording to claim
 3. 9. A method for treatment of non-insulin dependentdiabetes; which comprises administering to a patient in need of saidtreatment an effective amount of a compound according to claim
 4. 10. Amethod for treatment of non-insulin dependent diabetes; which comprisesadministering to a patient in need of said treatment an effective amountof a compound according to claim 5.